A flexible, modular route to cyclopentanols

Article abstract of DOI:10.1016/j.tetlet.2009.09.157

A flexible, modular route to cyclopentanols is devised based on a sequence of xanthate radical reactions followed by magnesium-mediated ketyl-olefin cyclization.

Full text of DOI:10.1016/j.tetlet.2009.09.157

Tetrahedron Letters 50 (2009) 6973–6976
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A flexible, modular route to cyclopentanols
*
Zhi Li, Samir Z. Zard
Laboratoire de Synthèse Organique, UMR 7652 CNRS-École Polytechnique, Route de Saclay, 91128 Palaiseau Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2009
Revised 16 September 2009
Accepted 25 September 2009
Available online 1 October 2009
A flexible, modular route to cyclopentanols is devised based on a sequence of xanthate radical reactions
followed by magnesium-mediated ketyl-olefin cyclization.
Ó 2009 Published by Elsevier Ltd.
Keywords:
Cyclopentanol
Xanthate
Magnesium
Ketyl-olefin cyclization
The intramolecular ketyl-olefin cyclization has proved to be a
useful tool in organic synthesis.1 In contrast to the numerous stud-
ies on the intramolecular ring closure of ketyl radicals to simple,2
could then undergo a 5-exo cyclization onto the vinyl group, or
whether an organomagnesium species would form first followed
by an ionic ring closure onto the ketone to furnish a chlorocycloh-
exenol or a product derived there from, Scheme 1.
or activated olefins such as
a
,b-unsaturated esters,3 nitriles,4 and
sulfides,4b,5 little attention has been paid to the cyclization of ketyl
radicals to halogenated alkenes. The presence of both the halide
and the ketone group introduces an uncertainty as to which group
As part of our work on the degenerative xanthate transfer reac-
tion,6 we conjectured that the requisite linear
c-dichlorovinyl-
substituted ketone 1 could be obtained rapidly from readily
Cl
Mg
O
Cl
OH
5-exo cyclization
R
R
Cl
Cl
?
O
R
Mg
Cl
O
Cl
Cl
1
HO
R
6-endo cyclization
?
Cl
R
MgCl
Scheme 1. Possible modes of cyclization of c-dichlorovinyl-substituted ketone 1 in the presence of magnesium.
is reduced first. For instance, in the case of
tuted ketone 1, it is not obvious whether reduction with metallic
magnesium would result in the creation of a ketyl radical, which
c
-dichlorovinyl-substi-
available xanthate 2 via a xanthate transfer addition, followed
by exchange of the xanthate group with a dichlorovinyl motif
through reaction with dichlorovinyl ethyl sulfone, as indicated in
Scheme 2.7
We started our study by preparing a series of xanthate deriva-
tives 3 via radical addition of xanthates 2a–c to various alkenes.
* Corresponding author. Tel.: +33 0 1 69335971; fax: +33 0 1 69335972.
E-mail address: zard@poly.polytechnique.fr (S.Z. Zard).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.09.157

6974
Z. Li, S. Z. Zard / Tetrahedron Letters 50 (2009) 6973–6976
O
SO2Et
Cl
Cl
S
O
O
SCOEt
R
R
10 mol% DLP
+
R
Cl
SCOEt
S
EtOAc
chlorobenzene
DTBP, reflux
reflux
2
Cl
3
1
DLP = dilauroyl peroxide
DTBP = di-tert-butyl peroxide
Scheme 2. Synthesis of c-dichlorovinyl-substituted ketone 1.
The reactions proceeded smoothly and in generally good yields, as
shown by the results compiled in Table 1 (Xa = SC(S)OEt).
When the reaction was conducted in THF or Et2O, no cycliza-
tion product was obtained and the starting material was recov-
ered quantitatively (entries 1 and 2). The generation of either
the ketyl or the Grignard intermediate did not seem straightfor-
ward under these conditions. In order to favor the creation of
the former species, a protic solvent was employed. Indeed, when
1a was treated with 4 equiv of Mg in methanol at room tempera-
ture, the 5-exo cyclization product 4a was obtained in 20% yield as
one major diastereoisomer (entry 3). Activation of the magnesium
with a small amount of HgCl210 caused an acceleration of the reac-
tion but did not result in a significantly improved yield of 4a (en-
try 4). When the reaction was conducted in methanol at reflux in
the presence of 10 equiv of Mg, cyclopentanol 4a was obtained
With xanthates 3 in hand, we set out to assemble the c-dichlo-
rovinyl-substituted ketones 1 via the radical reaction of 3 with 2,2-
dichlorovinyl ethyl sulfone.8 The desired key substrates 1 were ob-
tained in moderate to good yields (Table 2). In the case of xanthate
3g, the corresponding diastereoisomeric dichlorovinyl adducts 1g/
1g0 could be separated by chromatography.
We elected to use magnesium1c to generate the ketyl radical in
view of its convenience and low cost. In order to ascertain the via-
bility of cyclization of ketones 1 in the presence of Mg, adduct 1a
was selected as a model substrate and various reaction conditions
were screened as indicated in Table 3.
Table 1
Synthesis of xanthates 3
Entry
1
Substrate
Alkene
Product
Yielda (%)
77
O
O
TMS
TMS
TMS
Xa
2a
Xa
3a
3b
O
O
2
3
2a
2a
86b
81
TMS
Xa
Xa
3c
O
O
4
5
2a
2a
83
81
Xa
3d
Ph
Ph
Xa
3e
O
O
OMe
OMe
6
7
2a
71
OMe
OMe
Xa
3f
O
Xa
TMS
Xa
60b,c
TMS
3g
2b
O
O
TMS
Xa
8
87b
TMS
Xa
Ph
Ph
2c
3h
a
b
c
Isolated yield.
For syntheses of 3b, 3g and 3h, see: Ref. 9.
dr = 1:1.

Z. Li, S. Z. Zard / Tetrahedron Letters 50 (2009) 6973–6976
6975
Table 2
Synthesis of ketones 1 from xanthates 3 and dichlorovinyl ethyl sulfone
Table 3
Reactions of ketone 1a in the presence of Mg
Entry
Substrate
Product
Yielda (%)
Entry
Solvent
Mg/catalyst
Product (yield)a
1
2
THF (rt)
Et2O (rt)
4 equiv
4 equiv
Noneb
Noneb
O
TMS
1
3a
70
Cl
OH
Cl
Cl
1a
3
MeOH (rt)
4 equiv
O
Cl
TMS
TMS
2
3
3b
3c
55b
Cl
4a (20%)c
4a (20%)c
Cl
Cl
1b
4
5
6
7
8
9
10
11
MeOH (rt)
MeOH (reflux)
MeOH (rt)
4 equiv /HgCl2
10 equiv
4a (46%)c,d
4a (40%)c
4a (42%)c
4a (45%)c,e
4a (45%)c,f
4a (50%)c
4a (55%)c,g
O
20 equiv/HgCl2
20 equiv/HgCl2
20 equiv/HgCl2
20 equiv/HgCl2 NH4Cl
20 equiv/HgCl2
40 equiv/HgCl2
EtOH (rt)
63
MeOH/hexane (rt)
MeOH/hexane (rt)
MeOH (ꢀ23 °C)
MeOH (ꢀ23 °C)
Cl
1c
O
a
b
c
Isolated yield.
Starting material recovered.
4
5
3d
3e
33
65
dr = 5:1 was determined from the 1H NMR spectrum of the crude product.
Cl
Cyclopentanol 4a was isolated as the major isomer.
Cl
1d
d
The product was contaminated by small amounts of unidentified impurities
which could not be removed by flash column chromatography.
O
e
MeOH/hexane (v/v = 2:1).
40 equiv of NH4Cl were added.
For reaction details, see: Supplementary data.
f
Ph
g
Cl
Cl
1e
Cyclopentanols 4 with various substituents were obtained in
moderate to good yields according to this protocol. In all of these
derivatives, the 2-position was substituted with a dichloromethyl
group. No products bearing a monochloromethyl or a methyl
group in the 2-position were observed. This indicated that the
dichloromethyl group was inert to the presence of excess Mg un-
der our reaction conditions. The substituent at the 3-position of
cyclopentanols 4 can be alkyl (entries 1, 5, and 6), TMS (entry
2), or cycloalkyl (entries 3 and 4). Bicyclic alcohols such as 4g
and 4g0 can also be prepared efficiently by this method (entries
7 and 8). In all cases, the major diastereoisomer was the 1,2-trans
alcohol and the diastereomeric ratio was 5:1 to 4:1. Interestingly,
the two separated diastereoisomers 1g and 1g0 afforded the same
cyclization products in the same diastereomeric ratios (entries 7
and 8). This indicated that epimerization via the enolate of the
ketone was faster than ketyl generation. Indeed, thin layer chro-
matography indicated the equilibration of 1g and 1g0 under the
reaction conditions.
O
OMe
OMe
6
7
8
3f
75
Cl
Cl
1f
O
TMS
Cl
Cl
3g
3h
54b,c
1g/1g’
O
TMS
Ph
60b
Cl
Cl
1h
a
b
c
Isolated yield.
For syntheses of 1b, 1g/1g0 and 1h, see: Ref. 10.
dr = 1:1, 1g (Rf = 0.6, petroleum ether/EtOAc = 30:1), 1g0 (Rf = 0.5, petroleum
ether/EtOAc = 30:1). The ratio of 1g and 1g0 was determined from the 1H NMR
We next explored the cyclization of c-dichlorovinyl-substituted
phenyl ketone 1h. Unfortunately, only the simple ketone reduction
product 5 was obtained in 51% yield (Eq. 1). The ketyl radical is
clearly not sufficiently reactive with respect to cyclization while
further reduction is facilitated by the aromatic ring.
spectrum of the crude product.
along with unidentified impurities in 46% yield (entry 5). Increas-
ing the load of Mg but operating at room temperature did im-
prove the yield of 4a to 40% (entry 6) with respect to the same
reaction conducted with only 4 equiv of magnesium (entry 3).
Switching the solvent from methanol to ethanol, or to a mixture
of methanol and hexane (v/v = 2:1) did not result in any notice-
able improvement in yield (entries 7 and 8). Addition of NH4Cl
to the reaction mixture as a weak acid had no effect on the yield.
However, when the reaction temperature was lowered to ꢀ23 °C,
compound 4a was obtained in 50% yield (entry 10). This improved
result may be due to fewer side reactions at the lower tempera-
ture. Eventually, 4a was obtained in 55% yield when the reaction
was conducted in methanol at ꢀ23 °C in the presence of 40 equiv
of Mg (entry 11).
O
OH
TMS
10 equiv Mg
MeOH
TMS
Cl
Cl
Cl
51%
dr = 1:1
Cl
1h
5
ð1Þ
In summary, we have developed a flexible, modular route to
cyclopentanols based on a sequence of three radical reactions.
The first two exploit the unique ability of xanthates to mediate
intermolecular additions while the last is a magnesium-induced
ketyl-olefin cyclization. Various polyfunctional cyclopentanols
can be rapidly and efficiently assembled by simply modifying the
xanthate and olefinic partners in the first step.
With reasonably optimized reaction conditions in hand, we
examined the cyclization of the remaining substrates (Table 4).

6976
Z. Li, S. Z. Zard / Tetrahedron Letters 50 (2009) 6973–6976
Table 4
Syntheses of cyclopentanols 4
Acknowledgment
Entry
Substrate
Product
Yielda (%)
One of us (Z.L.) thanks Ecole Polytechnique for financial
support.
OH
Cl
OH
Cl
c
65b (99)
Supplementary data
Cl
Cl
1
1a
4a/4a0 = 5:1
TMS
TMS
Supplementary data (detailed experimental procedures and
characterization data for new compounds are provided) associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.09.157.
4a
4a'
OH
Cl
OH
Cl
2
3
1b
1c
Cl
Cl
60b
4b/4b0 = 5:1
References and notes
TMS
4b'
TMS
4b
1. For reviews, see: (a) Walton, J. C. Top. Curr. Chem. 2006, 264, 163–200; (b)
Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371–3403; (c)
Lee, G. H.; Choi, E. B.; Youn, I. K.; Yon, G. H.; Lee, H. K.; Yang, H. C.; Pak, C. S. Curr.
Org. Chem. 2004, 8, 1263–1287.
2. For some recent examples, see: (a) Sono, M.; Hanaoaka, M.; Hashimoto, T.;
Asakawa, Y.; Tori, M. Synlett 2009, 469–471; (b) Sadasivam, D. V.; Sudhadevi
Antharjanam, P. K.; Prasad, E.; Flowers, R. A., II J. Am. Chem. Soc. 2008, 130,
7228–7229; (c) Reissig, H.-U.; Khan, F. A.; Czerwonka, R.; Dinesh, C. U.; Shaikh,
A. L.; Zimmer, R. Eur. J. Org. Chem. 2006, 4419–4428; (d) Molander, G. A.;
George, K. M.; Monovich, L. G. J. Org. Chem. 2003, 68, 9533–9540; (e) Yadav, A.
K.; Singh, A. Synlett 2000, 1199–1201; (f) Watson, F. C.; Kilburn, J. D.
Tetrahedron Lett. 2000, 41, 10341–10345.
3. For some representative examples, see: (a) Inui, M.; Nakazaki, A.; Kobayashi, S.
Org. Lett. 2007, 9, 469–472; (b) Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.;
Matsuda, K.; Satake, M.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 11893–
11899; (c) Suzuki, K.; Nakata, T. Org. Lett. 2002, 4, 3943–3946; (d) Takahashi, S.;
Kubota, A.; Nakata, T. Angew. Chem., Int. Ed. 2002, 41, 4751–4754; (e) Kadota, I.;
Kadowaki, C.; Park, C.-H.; Takamura, H.; Sato, K.; Chan, P. W. H.; Thorand, S.;
Yamamoto, Y. Tetrahedron 2002, 58, 1799–1816.
4. (a) Yamamoto, Y.; Matsumi, D.; Hattori, R.; Itoh, K. J. Org. Chem. 1999, 64, 3224–
3229; (b) Lee, G. H.; Choi, E. B.; Lee, E.; Pak, C. S. J. Org. Chem. 1994, 59, 1428–
1443.
OH
Cl
56d (85)c
Cl
4c
OH
OH
Cl
Cl
Cl
Cl
4
5
6
1d
1e
1f
66b (74)c
4d/4d0 = 5:1
4d
4d'
OH
Cl
76d (81)c
Cl
Ph
4e
OH
5. Lee, G. H.; Ha, S. J.; Yoon, I. K.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2581–2584.
6. For general reviews, see: (a) Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205–213; (b)
Quiclet-Sire, B.; Zard, S. Z. Chem. Eur. J. 2006, 12, 6002–6016; (c) Quiclet-Sire, B.;
Zard, S. Z. Top. Curr. Chem. 2006, 264, 201–236; (d) Zard, S. Z.. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
Vol. 1, pp 90–108; (e) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur Silicon Relat.
Elem. 1999, 153, 137–145; (f) Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672–
685.
Cl
55d (78)c
Cl
MeO
4f
MeO
7. For the exchange of the xanthate group with
a dichlorovinyl motif, see:
Bertrand, F.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem., Int. Ed. 1999, 38, 1943–
1946; For a review, see: Bertrand, F.; Leguyader, F.; Liguori, L.; Ouvry, G.;
Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. C. R. Acad. Sci. Paris 2001, 114, 547–555.
8. For the synthesis of dichlorovinylethyl sulfone, see: (a) Kay, I. T.; Ponja, N. J.
Chem. Soc. C 1968, 3011–3014; (b) Schultz, H. S.; Freyermoth, H. B.; Buc, S. R. J.
Org. Chem. 1963, 28, 1140–1142.
Cl
OH
Cl
OH
Cl
Cl
7
8
1g
52b (82)c
TMS
TMS
4g/4g0 = 5:1
H
4g
H
4g'
9. Li, Z.; Zard, S. Z. Org. Lett. 2009, 11, 2868–2871.
10. Adams, R.; Adams, E. W. Org. Synth. Coll. Vol. 1 1941, 5, 459–461.
1g0
4g and 4g0
41b (63)c
4g/4g0 = 5:1
a
b
c
Isolated yield.
Total yield of the two diastereoisomers.
Yield based on recovered of starting material.
d
dr = 4:1 was determined from the 1H NMR spectrum of the crude product. The
product was isolated as the major isomer.